Many diseases, conditions and injuries are associated with reductions in the levels of antioxidant molecules and activity of antioxidant enzyme systems in affected tissues or organs and subsequent loss of cellular integrity secondary to oxidative stress. Oxidative stress represents an imbalance between production of reactive oxygen species and other oxidative molecules derived there from, for example lipid or other peroxides, and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive oxidant molecules or to repair the resulting damage. Reactive oxygen species can be beneficial, as they are used by the immune system as a way to attack and kill pathogens. In addition, some reactive oxidative species can act as intracellular or extracellular signaling molecules to trigger cellular responses through a process termed redox signaling. However, disturbances in the normal balance between oxidative and reductive processes in cells and tissues can cause toxic effects through excessive production of peroxides and free radicals that damage components of the cell, including proteins, carbohydrates, lipids, and DNA. Reduced antioxidant status may be a direct or indirect effect of a disease or insult. A deficiency of cellular antioxidants may lead to excess free radicals and other reactive oxygen species (ROS) the destructive effects of which can ultimately lead to cell death. The effects of oxidative stress depend upon the magnitude of the disturbance, with a cell being able to overcome small perturbations and regain its original state using natural antioxidant defenses, such as glutathione (GSH). GSH is synthesized by most cells and is one of the primary antioxidants responsible for maintaining the proper antioxidant status within the body.
However, under certain conditions, the normal physiologic supplies of GSH or other antioxidants are insufficient, the distribution is inadequate, or oxidative demands are too high to prevent cellular oxidation. Depressed antioxidant levels, either locally in particular cells or organs or systemically, have been associated with a number of clinically defined diseases and disease states which are the result of or which progress because of excessive free radical reactions and insufficient antioxidants.
Administration of reduced thiol containing compounds that provide either a substrate for generation of endogenous antioxidants such as glutathione, e.g. N-acetylcysteine, or are themselves directly or indirectly capable of scavenging reactive oxygen species, has been used to reestablish antioxidant status to ameliorate conditions of oxidative stress. However, chemical instability of thiol containing compounds limits shelf life under normal storage conditions, and particularly under extreme storage conditions and/or in common vehicles used for systemic administration. This property of chemical instability of thiol-containing antioxidants has limited widespread use of such compounds for treatment of disorders and diseases in which oxidative stress is a significant component of pathophysiology. Additionally, many thiol-containing antioxidant molecules and non-thiol antioxidant molecules have poor pharmaceutical properties, for example, low oral bioavailability or rapid clearance, which limits their utility.
Thus, there is a need for antioxidant compounds having improved pharmaceutical properties that are safe, potent, and stable even under extreme storage conditions, to normalize cellular antioxidant status in order to abrogate many of the untoward manifestations of the disease/injury associated with depletion of cellular oxidative defenses.